Cancer chemotherapy causes acute adverse effects (e.g. neutropenia, nausea, hair loss) which are treatable or are temporary. However, clinical evidence shows that cancer chemotherapy also causes chronic injury of many healthy organs and tissues (hematopoietic and immune systems, central and peripheral nervous system, pulmonary, gastrointestinal, cardiovascular and reproductive systems). These adverse effects limit the dose of chemotherapy drugs that can be given and diminish their efficacy to eradicate cancer. The chronic adverse aftereffects persist long after completion of therapy and jeopardize the long-term health of many patients. However, the characterization of adverse long-term effects of chemotherapy on the function of healthy tissues and organs, and the research on the causes and prevention of treatment related morbidities are just beginning. The International Agency for Cancer Research reported that the number of new cancer cases will rise from 14 to 19 million per year by 2025. Since the long-term survival rates of cancer patients continue to improve, the number of cancer survivors with long-term adverse consequences from chemotherapy is steadily increasing. According to ACS there are now over 13.7 million cancer survivors in the US, with that number expected to grow to 18 million by 2022. Steady increase in the frequency of patients surviving cancer necessitates characterization of long-term effects of chemotherapy on healthy tissues and organs and finding approaches to minimize them. This interdisciplinary and highly innovative project will utilize preclinical breast tumor-bearing mouse models combined with chemotherapy for breast cancer and mouse models of bacterial and viral infections to (1) define long-lasting effects of chemotherapy on the function of hematopoietic and immune systems and their responses to new and recurring infections, (2) investigate the role of inflammation in causing chemotherapy- induced long-term adverse sequelae in the hematopoietic and immune systems, and test whether (3) concurrent administration of chemotherapy and anti-inflammatory drugs, and novel targeted delivery of chemotherapy drugs into the primary tumors represent effective new strategies to decrease or prevent chemotherapy-induced long-term adverse sequelae. The outcomes of this research could provide a significant platform for translational and clinical testing of (a) anti-inflammatory treatment as new adjunct therapy for cancer patients undergoing chemotherapy, and (b) novel targeted delivery of chemotherapy drugs into the primary tumors as new approaches to (1) reduce treatment-related long-term sequelae, (2) improve treatment efficacy, (3) increase cancer cure rate, and (4) improve the long-term health of cancer patients.